This invention relates to certain quinazoline compounds as well as the pharmaceutically acceptable salts thereof. The compounds of the present invention inhibit the action of certain growth factor receptor protein tyrosine kinases (PTK) thereby inhibiting the abnormal growth of certain cell types. The compounds of this invention are therefore useful for the treatment of certain diseases that are the result of deregulation of these PTKs. The compounds of this invention are anti-cancer agents and are useful for the treatment of cancer in mammals. In addition, the compounds of this invention are useful for the treatment of polycystic kidney disease in mammals. This invention also relates to the manufacture of said quinazolines, their use for the treatment of cancer and polycystic kidney disease, and the pharmaceutical preparations containing them.
Protein tyrosine kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP to a tyrosine residue located on a protein substrate. Protein tyrosine kinases clearly play a role in normal cell growth. Many of the growth factor receptor proteins function as tyrosine kinases and it is by this process that they effect signaling. The interaction of growth factors with these receptors is a necessary event in normal regulation of cell growth. However, under certain conditions, as a result of either mutation or overexpression, these receptors can become deregulated; the result of which is uncontrolled cell proliferation which can lead to tumor growth and ultimately to the disease known as cancer [Wilks A. F., Adv. Cancer Res., 60, 43 (1993) and Parsons, J. T.; Parsons, S. J., Important Advances in Oncology, DeVita V. T. Ed., J. B. Lippincott Co., Phila., 3 (1993)]. Among the growth factor receptor kinases and their proto-oncogenes that have been identified and which are targets of the compounds of this invention are the epidermal growth factor receptor kinase (EGF-R kinase, the protein product of the erbB oncogene), and the product produced by the erbB-2 (also referred to as the neu or HER2) oncogene. Since the phosphorylation event is a necessary signal for cell division to occur and since overexpressed or mutated kinases have been associated with cancer, an inhibitor of this event, a protein tyrosine kinase inhibitor, will have therapeutic value for the treatment of cancer and other diseases characterized by uncontrolled or abnormal cell growth. For example, overexpression of the receptor kinase product of the erbB-2 oncogene has been associated with human breast and ovarian cancers [Slamon, D. J., et. al., Science, 244, 707 (1989) and Science, 235, 1146 (1987)]. Deregulation of EGF-R kinase has been associated with epidermoid tumors [Reiss, M., et. al., Cancer Res., 51, 6254 (1991)], breast tumors [Macias, A., et. al., Anticancer Res., 7,459 (1987)], and tumors involving other major organs [Gullick, W. J., Brit. Med. Bull., 47, 87 (1991)]. Because the importance of the role played by deregulated receptor kinases in the pathogenesis of cancer, many recent studies have dealt with the development of specific PTK inhibitors as potential anti-cancer therapeutic agents [some recent reviews: Burke. T. R., Drugs Future, 17, 119 (1992) and Chang, C. J.; Geahlen, R. L., J. Nat. Prod., 55, 1529 (1992)].
It is also known that deregulation of EGF receptors and abnormal location of these receptors are a factors in the growth of epithelial cysts in the disease described as polycystic kidney disease [Du J., Wilson P. D., Amer. J. Physiol., 269(2 Pt 1), 487 (1995); Nauta J., et al., Pediatric Research, 37(6), 755 (1995); Gattone V. H., et al., Developmental. Biology, 169(2), 504 (1995); Wilson P. D., et al., Eur. J. Cell Biol., 61(1), 131, (1993)]. The compounds of this invention, which inhibit the catalytic function of the EGF receptors, are consequently useful for the treatment of this disease.
In addition to the above utilities some of the compounds of this invention are useful as intermediates for the preparation of other compounds of this invention.
The compounds of this invention are certain substituted quinazolines. Throughout this patent application, the quinazoline ring system is numbered as indicated in the formula below: ##STR2##
A number of 4-anilinoquinazolines which differ both in the nature and placement of the substituents at positions 5-8 compared to the compounds of this invention have been noted to have PTK inhibitory activity. The application EP-92305703.8 describes 4-anilinoquinazolines that contain simple substituents such as chloro, trifluoromethyl, or nitro groups at positions 5 to 8. The application EP-93300270.1 is similar but with a much larger variety of substituents allowed at positions 5 to 8. The application WO-9609294 describes compounds with similar substituents at positions 5 to 8 and with the substituent at to 4-position consisting of certain polycyclic ring systems. Some simple substituted quinazolines are also described in the applications WO-9524190, WO-9521613, and WO-9515758. The applications EP-93309680.2 and WO-9523141 cover similar quinazoline derivatives where the aryl group attached at position 4 can be a variety of heterocyclic ring structures. The application EP-94305195.3 describes certain quinazoline derivatives that have alkenoylamino and alkynoylamino groups among the substituents at position 6 but require a halogen atom at position 7. The application WO-9519774 describes compounds where one or more of the carbon atoms at positions 5-8 are replaced with heteroatoms resulting in a large variety of bicyclic systems where the left-hand ring is a 5 or 6-membered heterocyclic ring; in addition, a variety of substituents are allowed on the left-hand ring. The application EP-682027-A1 describes certain pyrrolopyrimidine inhibitors of PTKs. The application WO-9519970 describes compounds in which the left-hand aromatic ring of the basic quinazoline structure has been replaced with a wide variety of different heterocyclic rings so that the resulting inhibitors are tricyclic. The application WO-94305194.6 describes quinazolines where an additional 5 or 6-membered heterocyclic ring with optional substitution is fused at positions 5 and 6. The application WO-9633981 describes 4-anilino quinazolines that have at the 6-position various alkoxyalkylamino groups. The application WO-9633980 describes 4-anilino quinazolines that have at the 6-position various aminoalkylalkoxy groups. The application WO-9633979 describes 4-anilino quinazolines that have at the 6-position various alkoxyalkylalkoxy groups. The application WO-9633978 describes 4-anilino quinazolines that have at the 6-position various aminoalkylamino groups. The application WO-9633977 describes 4-anilino quinazolines that have at the 6-position various aminoalkylalkoxy groups. It is noteworthy that none of the compounds in the aforementioned applications have the unique combination of substituents contained in the compounds of the present invention.
In addition to the aforementioned patent applications, a number of publications describe 4-anilinoquinazolines: Fry, D. W., et. al., Science, 265, 1093 (1994), Rewcastle G. W., et. al., J. Med. Chem., 38, 3482 (1995), and Bridges, A. J., et. al., J. Med. Chem., 39, 267, (1996). None of the compounds described in these publications have the unique combination of substituents contained in the compounds of the present invention. In addition, it is noteworthy that no demonstration of an in vivo anti-cancer effect is described in these reports.
A PTK catalyses the transfer of a phosphate group from a molecule of ATP to a tyrosine residue located on a protein substrate. The inhibitors so far known in the art are usually competitive with either the ATP or the protein substrate of the kinase. Some of these inhibitors, the so-called mixed competitive inhibitors, can be competitive with both ATP and substrate simultaneously; all such competitive inhibitors function as reversible inhibitors. The 4-anilinoquinazolines known in the art are reversible inhibitors that are competitive with ATP [Fry, D. W., et. al., Science, 265, 1093 (1994)]. Since the concentration of ATP in a cell is normally very high (millimolar), compounds that are competitive with ATP may show poor in vivo activity since it is unlikely that said compounds can reach the concentrations within the cell for the extended period of time that would be necessary to displace the ATP from its binding site for a long enough time to inhibit tumor growth. Unlike the more conventional quinazoline inhibitors, the quinazoline inhibitors of this invention have the unique ability of inhibiting these PTKs in an irreversible manner and are therefore non-competitive with ATP or protein substrate. The compounds of this invention can function as irreversible inhibitors by virtue of the fact that they can form covalent bonds to amino acid residues located at the active site of the enzyme. This can result in an enhanced therapeutic usefulness of the compounds of this invention when compared to the reversible type of inhibitor. In particular, it is the unique nature and combination of substituents contained in the compounds of the present invention that lead to the irreversible binding of the inhibitor to the enzyme.